Therapeutic patch

ABSTRACT

The invention relates to a topical patch comprising a therapeutic compound-impermeable backing layer, a self-adhesive matrix based on polysiloxanes and containing capsaicin or a therapeutic compound analogous to capsaicin, and a protective film to be removed before use, in which the matrix contains liquid microreservoirs based on an amphiphilic solvent, in which the therapeutic compound is present in completely dissolved form and the concentration of the therapeutic compound in the microreservoir droplets is below the saturation concentration. The invention furthermore relates to a process for its production and its use in the treatment of neuropathic pain.

BACKGROUND

[0001] Neuropathic pain is believed to result from sensitizationreactions in the peripheral and central nervous system. Such pain canoccur as a result of peripheral injuries, or as a result of systemicdiseases such as HIV, herpes zoster, syphilis, diabetes and autoimmunediseases. Neuropathic pain can be severe and is often debilitating, andeffective methods for reducing neuropathic pain would amelioratesignificant suffering.

[0002] In U.S. Pat. No. 6,248,788 (Robbins et al.), a topical method oftreatment of neuropathic pain with capsaicin or substances analogous tocapsaicin is described. The Robbins et al. patent disclosed thattreatment of the affected body areas once or at most twice with a highlyconcentrated capsaicin preparation for a few hours eliminates orsignificantly alleviates the pain for a number of weeks. It is believedthe basis for this treatment is that the nerve fibers necessary orresponsible for the pain sensation (C fibers) are desensitized by thecapsaicin (or capsaicin analog) and degenerate. However, this effectonly occurs when the active compound concentration in the C fibers ishigh enough. Conventional topical preparations containing capsaicin donot optimally fulfill these requirements, as they release too littlecapsaicin on the skin and the active compound concentration in the Cfibers remains below the effective concentration.

[0003] U.S. Pat. No. 6,239,180 (Robbins) describes the use oftherapeutic patches comprising capsaicin and/or a capsaicin analog at aconcentration of greater than 5% to 10% by weight for treatment ofneuropathic pain. The object was thus to develop a patch which issuitable and optimized for the topical therapy of neuropathic pain andother conditions.

BRIEF DESCRIPTION OF THE FIGURES

[0004]FIGS. 1-3 are diagrams showing construction of a microreservoirsystem.

DETAILED DESCRIPTION

[0005] The invention relates to a drug delivery device suitable foradministrating capsaicin, a capsaicin analog, or a mixture thereof. Forconvenience, the term “therapeutic compound” is sometimes used hereinbelow to refer to capsaicin, capsaicin analog(s), or mixtures to beadministered. In one aspect, the invention provides a drug deliverydevice comprising a therapeutic compound-impermeable backing layer, aself-adhesive matrix (usually a polysiloxane-based matrix) comprisingindividual isolated liquid microreservoir droplets (“microreservoirs”)containing capsaicin or a capsaicin analog dissolved in an amphiphilicsolvent, and a protective film to be removed before use of the device.The term “microreservoir system” used herein refers to the saidself-adhesive matrix comprising a plurality of the said microreservoirdroplets which are microdispersed in the matrix. The active compound(e.g., capsaicin) in the microreservoir droplets is dissolved at aconcentration below the saturation concentration (and is thus present incompletely dissolved form).

[0006] In a related aspect, the invention provides a method of treatingneuropathic pain in a subject (e.g., human, non-human, primate, ormammal) in need of such treatment by applying a device of the invention.

[0007] In another related aspect, the invention provides a method ofmaking a drug delivery device suitable for treatment of neuropathicpain.

[0008] A brief discussion of the architecture of therapeutic patcheswill aid in the appreciation of the present invention. Various forms oftopical and transdermal patches are known for delivering an activecompound (e.g., drug), the most common being “matrix systems” and“reservoir systems”.

[0009] Matrix systems are characterized (in the simplest case) by abacking layer impermeable to the active compound (i.e., compound to bedelivered to the subject), an active compound-containing layer and aprotective layer to be removed before use. The activecompound-containing layer contains the active compound completely orpartially in dissolved form and is ideally self-adhesive. In morecomplicated embodiments, the matrix is composed of a number of layersand can include a control membrane. Suitable base polymers for aself-adhesive matrix are, for example, polyacrylates, polysiloxanes,polyurethanes or polyisobutylenes.

[0010] Reservoir systems are a type of pouch consisting of animpermeable and inert backing layer and an active compound-permeablemembrane, the active compound being present in a liquid preparation inthe pouch. The membrane can be a microporous film or a nonporouspartition membrane. Usually, the membrane is provided with an adhesivelayer that serves to adhere the system to the skin. The side facing theskin is also protected in this patch design by a film that has to beremoved before use.

[0011] An advantage of the reservoir systems is that the saturationsolubility of the active compound can be adjusted easily to theparticular need by the choice of the solvent or solvent mixture. Forthermodynamic reasons, it is advantageous for the release of activecompound in and on the skin if the active compound is present in theactive compound-containing parts of the patch at a concentration that isnot too far below the saturation concentration. The uptake capacity ofthe patch for the amount of active compound needed can be adjusted in awide range to fit the particular needs by means of adjusting the amountof active compound solution.

[0012] In matrix patches, the active compound is included in theadhesive matrix in a form that is safe from leaking, and the patch canbe cut to the size using ordinary scissors. On the other hand, it isdifficult under certain circumstances to adjust the solubilityproperties of the matrix for the active compound such that the activecompound can be dissolved in the matrix in the necessary amount and alsoremains dissolved during the storage. In the case of a patch to delivercapsaicin or an analog, the therapeutic compound present in the matrixin undissolved form, or which recrystallizes during the storage period,makes no contribution to the release of

[0013] The proportion of the microreservoir droplets in the matrix isusually less than about 40% by weight, more often less than about 35% byweight and most often between about 20 and about 30% by weight.

[0014] Amine-resistant polysiloxanes can be used in the matrix.Preferably, a mixture of a polysiloxane of medium tack and apolysiloxane of high tack is used. The used polysiloxanes aresynthesized from linear bifunctional and branched polyfunctionaloligomers. The ratio of both types of oligomers determines the physicalproperties of the adhesives. More polyfunctional oligomers result in amore cross-linked adhesive with a higher cohesion and a reduced tack,less polyfunctional oligomers result in a higher teack and a reducedcohesion. The high tack version used in the examples is tacky enough tostick on human skin. The medium tack version is nearly not tacky at allbut is useful to compensate the softening effect of other ingredientslike e.g. in this case of capsaicin and the solvent of themicroreservoirs. To increase the adhesive power of the matrix, this cancontain 0.5-5% by weight of a silicone oil (e.g., dimethicone).

[0015] In a preferred embodiment of a topical patch according to theinvention, the matrix contains at least 5% to about 10% by weight ofcapsaicin or capsaicin analog, 10-25% by weight of diethylene glycolmonoethyl ether, 0-2% by weight of ethylcellulose, 0-5% by weight ofsilicone oil and 58-85% by weight of self-adhesive pressure sensitivepolysiloxane. The coating weight of the matrix is usually between 30 and200 g/m², preferably between 50 and 120 g/m². Suitable materials for thebacking layer include, for example, a polyester film (e.g., 10-20 μmthick), an ethylene-vinyl acetate copolymer, and the like.

[0016] Suitable capsaicin analogs for use in the patches of theinvention include naturally occurring and synthetic capsaicinderivatives and analogs (“capsaicinoids”) such as, for example, thosedescribed in U.S. Pat. No. 5,762,963, which is incorporated herein byreference.

[0017] In microreservoir systems, a liquid active compound preparationis dispersed in an adhesive matrix in the form of small droplets(“microreservoirs”). The appearance of a microreservoir system issimilar to a classical matrix system, and a microreservoir system canonly be recognized from a typical matrix system with difficulty, sincethe small microreservoirs can only be recognized under the microscope.In the preceding and the following sections therefore, the activecompound-containing part of the patch is also described by “matrix”. Thesize of the resulting droplets depends on the stirring conditions andthe applied shear forces during stirring. The size is very consistentand reproducable using the same mixing conditions.

[0018] It is, however, to be noted that unlike classical matrix systems,in microreservoir systems the active compound is dissolved mainly in themicroreservoirs (and only to a small extent in the polymer). In thissense, microreservoir systems can be considered a mixed type of matrixpatch and reservoir patch and combines the advantages of both patchvariants. As in classical reservoir systems, the saturation solubilitycan easily be adjusted by the choice of the solvent to a valve adequatefor the particular requirements, and as in classical matrix systems thepatch can be divided into smaller patches using scissors withoutleakage.

[0019] Microreservoir systems can also include a control membranecontrolling the release of active compound and excipient. However, forthe specific application in the present case (i.e., having a shortapplication time in which is as rapid release of active compound isdesired) a control membrane usually not present.

[0020] Microreservoirs systems are disclosed in U.S. Pat. Nos.3,946,106, 4,053,580, 4,814,184 and 5,145,682, each of which isincorporated herein by reference. Specific microreservoirs systems aredescribed in international patent publication WO-A-01/01,967 thedisclosure of which is incorporated herein by reference. Thesemicroreservoir systems contain, as base polymer, polysiloxanes andamphiphilic solvents for the microreservoir droplets. It has now beendiscovered that such microreservoir systems are particularly highlysuitable, on the basis of the good solubility of capsaicin and capsaicinanalogs in amphiphilic solvents such as, for example, diethylene glycolmonoethyl ether, 1,3-butanediol, dipropylene glycol and Solketal, for atopical high concentration therapy using these active compounds. Aparticularly highly suitable solvent has proven to be diethylene glycolmonoethyl ether (DGME, also known by the trade name Transcutol®). Thesolubility of capsaicin in DGME is about 50% by weight, and thesolubilities of capsaicin analogs structurally similar to capsaicin arecomparable. This means that in order to incorporate enough activecompound into the matrix, the therapeutic compound does not necessarilyhave to dissolve in DGME in a concentration near the saturation limit.The result is that the patch itself is not amenable to recrystallizationof the therapeutic compound (e.g., capsaicin) even under unfavorableconditions, such as, for example, the partial loss of the solvent or lowtemperature. In practice, an about 20-35 % by weight solution ofcapsaicin in DGME has proven particularly highly suitable. Because thesaturation concentration of capsaicin in DGME is 50% by weight, thissolution is 40-70 % by weight of the saturation solubility. In thiscontext, the concentration is calculated according to the followingformula:

Weight of therapeutic compound×100/ (weight of therapeuticcompound+weight of solvent)

[0021] An advantage of using DGME is that, in addition to the highsaturation limit of capsaicin in this compound, DGME acts as apenetration enhancer. It is therefore advantageous that afterapplication of the patch to the skin, DGME is released along with thecapsaicin or analog. The simultaneous release of DGME causes theconcentration, and thus also the thermodynamic activity of thetherapeutic compound in the microreservoir system, to remain at a highlevel despite release. As the results of permeation experiments on humanepidermis shown in Table 2 demonstrate, the active compound flux fromsuch systems is approximately twice as high as that from a matrix whichis supersaturated with crystalline capsaicin. This is an indication thatthe active compound concentration in the microreservoir system increaseseven above the saturation solubility and the system even becomessupersaturated with dissolved capsaicin. Because of the shortapplication time, the therapeutic compound, however, has no opportunityto recrystallize, such that the active compound flux into the skin orthe active compound dispersion into the skin is very effective. Therapid increase of the concentration of the active compound in the activecompound reservoirs due to the fast release of DGME after theapplication of the patch is the final reason why the initialconcentration of the active compound can be well below the saturationconcentration without that the active compound flux is adverselyaffected. The absorption of moisture from the skin makes a furthercontribution. Because of the extremely low absorption capacity ofpolysiloxanes for water, moisture can only migrate into themicroreservoirs. Water is a very poor solvent for capsaicin and mostcapsaicin analogs. As a result, the saturation concentration of thetherapeutic compound in the microreservoirs is lowered and thus itsthermodynamic activity of the therapeutic compound is increased.

[0022] In order that these mechanisms can be effective, it is importantthat diffusible substances in the polymer have a high diffusioncoefficient. For this reason, polysiloxanes as base polymers areprefered to all other polymers now in use for microreservoir systems.

[0023] Polysiloxanes can be made from solvent-free two-component systemsor a solution in organic solvents. For patch production, self-adhesivepolysiloxanes dissolved in solvents are preferred.

[0024] These exist in two fundamentally different variants ofpolysiloxanes: the normal polysiloxane which have free silanol groups asshown in formula I,

[0025] and the “amine-resistant variants”, which are distinguished inthat the free silanol groups are derivatized by trimethylsilyl groups.Such amine-resistant polysiloxanes have also proven suitable fortherapeutic compound-containing patches without active compound and/orexcipients which both do not have a basic group. Owing to the absence offree silanol groups, the solubility of active compounds in the polymeris further reduced and the diffusion coefficient is further increasedfor many therapeutic compounds due to the interaction with the polarfree silanol groups, which is not possible. Formula I shows thestructure of a linear polysiloxane molecule that is prepared fromdimethylsiloxane by polycondensation. Three-dimensional crosslinking canbe achieved by the additional use of methylsiloxane.

[0026] In further polysiloxanes according to the invention, the methylgroups can be completely or partially replaced by other alkyl radicalsor alternatively phenyl radicals.

[0027] Without the invention being restricted thereto, the fundamentalmatrix composition of an embodiment of a patch according to theinvention containing the therapeutic compound capsaicin can be seen fromTable 1 below. TABLE 1 Composition of the matrix of a microreservoirsystem for the topical high-dose therapy of capsaicin Component Percentby weight Capsaicin 8 Transcutol ® (DGME) 20 Self-adhesive polysiloxane72 matrix

[0028] The thickness of the matrix is generally between about 30 andabout 200 μm (corresponding to a coating weight of about 30 to about 200g/m²), but values differing therefrom can also be used depending on theproperties of the specific formulation. In practice, a matrix thicknessof between 50 and 100 μm has proven particularly highly suitable. Thebacking layer for the patch should ideally be as impermeable or inert aspossible for the therapeutic compound and DGME or the amphiphilicsolvent selected. Polyester fulfills this condition, but other materialssuch as, for example, ethylene-vinyl acetate copolymers and polyamideare suitable. In practice, a polyester film about 20 μm thick has provenhighly suitable. In order to improve the adhesion of the matrix to thebacking layer, it is advantageous to siliconize the contact side of thebacking layer to the matrix. Adhesives based on polyacrylates do notadhere to such siliconized films or only adhere very poorly, adhesivesbased on polysiloxanes, however, adhere very well on account of thechemical similarity.

[0029] As the protective film to be removed before use, a polyester filmis best used which due to a specific surface treatment is repellent toadhesives based on polysiloxanes. Suitable films are supplied by anumber of manufacturers and are known best to the person skilled in theart.

[0030] The self-adhesive polysiloxane matrix can be a mixture ofadhesives having different adhesive behavior in order to optimize theadhesive behavior of the patch to the skin. For further improvement ofthe adhesive behavior, a silicone oil of suitable viscosity or molecularweight can additionally be added in a concentration of up to about 5% byweight.

[0031] The invention also relates to a process for the production of atopical patch according to the invention, which comprises dissolving thetherapeutic compound in an amphiphilic solvent, adding this solution toa solution of a polysiloxane or the matrix constituents and dispersingwith stirring, coating the resulting dispersion onto a protective layerwhich is removable and removing the solvent of the polysiloxane atelevated temperature and laminating the backing layer onto the driedlayer.

[0032] The solvent for the therapeutic compound must not mix or may onlymix to a small extent with the solvent for the adhesive. Suitablesolvents for adhesives are, for example, petroleum ethers or alkanessuch as n-hexane and n-heptane. It has been shown that the dispersion ofthe therapeutic compound solution can be realized more easily if theviscosity of the therapeutic compound solution is increased by theaddition of a suitable agent such as, for example, a cellulosederivative such as ethylcellulose or hydroxypropylcellulose. Thedispersion is now coated onto the removable protective film in athickness, which after the removal of the solvent of the adhesive,affords a matrix layer having the desired thickness. The dried layer isnow laminated with the backing layer and thus the finished patchlaminate is obtained.

[0033] The patches can now be punched out of this laminate in thedesired shape and size and packed into a suitable sachet of primarypacking. A highly suitable primary packing has proven to be a laminateconsisting of paper/glue/aluminum foil/glue/Barex®, as is described inU.S. Pat. No. RE37,934. Barex® is a heat-sealable polymer based onrubber-modified acrylonitrile copolymer, which is distinguished by a lowabsorptivity for volatile ingredients of patches. The aim of theinvention was the development of a patch having an optimized therapeuticcompound flux into the human skin. Because the microreservoir systemwithin the meaning of this invention has no membrane controlling therelease of therapeutic compound, and also the matrix itself can exert nokinetic control on the release of therapeutic compound due to the highdiffusion coefficient of the therapeutic compound in polysiloxanes, theonly element controlling the release of therapeutic compound into thedeeper skin layers is the skin or the uppermost layer of skin or theuppermost layer of skin, the stratum corneum. The optimization of thematrix composition was therefore consistently carried out by in vitropermeation studies using human skin and by Franz diffusion cells knownto the person skilled in the art for the experimental procedure.

[0034] In a first study, the influence of DGME on the permeation ratewas investigated. The results are shown in Table 2. TABLE 2 Influence ofDGME on the permeation rate of capsaicin through human epidermis⁽¹⁾Cumulated amount of capsaicin Permeation [μg/cm²]⁽²⁾ after rateFormulation 1 h 2 h 3 h 4 h 6 h 8 h [μg/cm² * h] Formula- 0.72 2.37 4.245.93 9.37 12.70 1.59 tion 1⁽³⁾ (with DGME) Formula- 0.34 1.09 1.96 2.794.52 6.32 0.79 tion 2⁽⁴⁾ (without DGME)

[0035] In formulation 2, the therapeutic compound capsaicin is largely(>95% by weight) dispersed in the matrix undissolved in the form ofsmall crystals. This means that the matrix is saturated with dissolvedcapsaicin and the thermodynamic activity of the therapeutic compound ismaximal for a stable matrix which is not supersaturated. Formulation 1shows a permeation rate that is approximately twice as high.

[0036] Ignoring the small amounts of capsaicin that are dissolved in thepolysiloxane itself, the concentration of the capsaicin in themicroreservoir droplets in formulation 1 is about 28% by weight. This isconsiderably below the saturation solubility of 50% by weight andguarantees that even in the case of a partial loss of the DGME or atreduced temperature there is no danger of recrystallization in thematrix. This means that before use the patch is physically stable andreaches a higher saturated or supersaturated state associated with agreatly increased permeation rate only after application.

[0037] In a second series, the influence of the capsaicin concentrationon the permeation rate was investigated. The results are shown in Table3. TABLE 3 Influence of the capsaicin concentration on the permeationrate through human epidermis⁽¹⁾ Cumulated amount of capsaicin Permeation[μg/cm²]⁽²⁾ after rate Formulation⁽³⁾ 1 h 2 h 3 h 4 h 6 h 8 h [μg/cm² *h] Formulation 3 0.32 0.69 1.0 1.44 2.15 2.98 0.37 4% by weight ofcapsaicin Formulation 4 0.30 0.74 1.40 1.71 2.77 3.93 0.49 6% by weightof capsaicin Formulation 5 0.54 1.02 1.72 2.37 3.44 4.64 0.58 8% byweight of capsaicin

[0038] The permeation rate shows a marked dependence on the capsaicinconcentration, i.e. the release rate of the patch can be adjusted easilyto the value necessary for capsaicin or capsaicin analog via theconcentration in DGME (or the solvent intended for the microreservoirs).

[0039] A capsaicin concentration of about 8% by weight (e.g., about 5%to about 10% by weight, usually 7% to 9% by weight) in combination witha DGME concentration of about 15% to about 25% by weight has provenparticularly highly suitable.

[0040] A therapeutic compound-containing matrix optimized with respectto the adhesive behavior on the skin and the other physical propertieshas the following composition: TABLE 4 Optimized composition of thematrix of a microreservoir system for topical high-dose therapy usingcapsaicin Component Percent by weight capsaicin 8 DGME 20 Ethylcellulose0.8 High-tack amine-resistant 21 polysiloxane BIO-PSA 4301, Dow CorningMedium-tack amine-resistant 49 polysiloxane BIO-PSA 4201, Dow CorningSilicone oil, 12,500 cSt 2 Coating weight 80 g/m²

[0041] Patches within the meaning of this invention containing thetherapeutic compound capsaicin have proven very effective in appropriateclinical studies. Even a one-hour treatment of the affected areasreduced the sensation of pain significantly, the action lasting forweeks. The patches in this case proved to be highly tolerable and werevery well accepted by the patients. In summary, it can thus be said thatpatches within the meaning of this invention are optimally suitable fortreatment of neuropathic pain described in U.S. Pat. No. 6,248,788 usinghigh concentration of capsaicin or capsaicin analogs.

[0042] The invention therefore also relates to use of a topical patchaccording to the invention for the treatment of neuropathic pain andother conditions.

Use of the Capsaicon or Capsaicin Analog Patch

[0043] This section describes use of the invention. However, it will beunderstood that the examples in this section are provided forillustration and not limitation. Capsaicin application has numeroustherapeutic benefits, each of which can be effectively treated using themethods of the invention. Conditions for which capsaicin or capsaicinanalog treatment may be indicated include neuropathic pain (includingpain associated with diabetic neuropathy, postherpetic neuralgia,HIV/AIDS, traumatic injury, complex regional pain syndrome, trigeminalneuralgia, erythromelalgia and phantom pain), pain produced by mixednociceptive and/or neuropathic mixed etiologies (e.g., cancer,osteoarthritis, fibromyalgia and low back pain), inflammatoryhyperalgesia, interstitial cystitis, dermatitis, pruritis, itch,psoriasis, warts, and headaches. Generally, the capsaicin- or capsaicinanalog-containing patches can be used to treat any condition for whichtopical administration of capsaicin is beneficial.

EXAMPLES

[0044] The following examples serve to illustrate the invention withoutthe latter having to be restricted thereto.

Example 1 Production of a Patch Containing Capsaicin

[0045] 250 g of DGME are initially thickened with 4.5 g ofethylcellulose with stirring. 97 g of capsaicin is then added andcompletely dissolved with stirring. 286 g of the above therapeuticcompound solution is added to 1000 g of a solution of the polysiloxaneor the mixture of the polysiloxanes in n-heptane having a solids contentof 70% by weight and dispersed in the adhesive solution with intensivestirring.

[0046] Subsequently, using a suitable coating process, the dispersion iscoated onto a removable protective film and is suitable for polysiloxaneadhesives, e.g. Scotchpak® 1022 from 3M, in a thickness such that thecoating weight after the removal of the n-heptane is 80 g/ m². The driedfilm is then laminated with the backing layer, e.g. polyester film 20 μmthick, and the finished patch is punched out of the complete laminate.The punched patches are then sealed into a sachet of a suitable primarypacking laminate.

[0047] The temperatures under which the solvent of the adhesive,n-heptane, is removed, should ideally not exceed 40° C. There is moreDGME in the final bulk mixture than in the final composition due to lossof DGME during the drying process.

Example 2

[0048] 196 g of DGME is initially thickened with 4 g of ethylcellulosewith stirring. 30 g of nonivamide (pelargonic acid vanillylamide) arethen added and completely dissolved with stirring.

[0049] The solution is then added to 1000 g of a solution of thepolysiloxane or the mixture of the polysiloxanes in n-heptane having asolids content of 70% by weight and dispersed in the adhesive solutionwith intensive stirring.

[0050] Subsequently, using a suitable coating process, the dispersion iscoated onto a removable protective film, e.g. Scotchpak® 1022 from 3M,in a thickness such that the coating weight after the removal of then-heptane is 100 g/m². The dried film is then laminated with the backinglayer, e.g. polyester film 20 μm thick, and the finished patch ispunched out of the complete laminate. The punched patches are thensealed into a sachet of a suitable primary packaging.

Example 3

[0051] 200 g of dipropyleneglycol are thickened with 2 g ofhydroxyethylcellulose with stirring. 60 g of capsaicin is then added andcompletely dissolved with stirring. The solution is then added to 1000 gof a solution of the polysiloxane or the mixture of the polysiloxanes inn-heptane having a solids content of 70% by weight and dispersed in theadhesive solution with intensive stirring.

[0052] Subsequently, using a suitable coating process, the dispersion iscoated onto a removable protective film, e.g. Scotchpak® 1022 from 3M,in a thickness such that the coating weight after the removal of then-heptane is 100 g/m². The dried film is then laminated with the backinglayer, e.g. polyester film 20 μm thick, and the finished patch ispunched out of the complete laminate. The punched patches are thensealed into a sachet of a suitable primary packaging.

Example 4

[0053] Same procedure as described in example 1 but olvanil (oleylvanillylamide) is used instead of capsaicin.

Example 5

[0054] 36 g of nonivamide is dissolved in 164 g of Solketal withstirring. The solution is then added to 1000 g of a solution of thepolysiloxane or the mixture of the polysiloxanes in n-heptane having asolids content of 70% by weight and dispersed in the adhesive solutionwith intensive stirring.

[0055] Subsequently, using a suitable coating process, the dispersion iscoated onto a removable protective film, e.g. Scotchpak® 1022 from 3M,in a thickness such that the coating weight after the removal of then-heptane is 100 g/m². The dried film is then laminated with the backinglayer, e.g. polyester film 20 μm thick, and the finished patch ispunched out of the complete laminate. The punched patches are thensealed into a sachet of a suitable primary packaging.

1. A topical patch comprising a therapeutic compound-impermeable backinglayer, a self-adhesive matrix based on polysiloxanes containing at least1% by weight, preferably at least 2% by weight, more preferably at least3% by weight, most preferably at least 5% by weight, of the therapeuticcompound, and a protective film to be removed before use, in which a.the matrix contains liquid microreservoir droplets comprising anamphiphilic solvent, in which the therapeutic compound is dissolved, andb. the concentration of the therapeutic compound in the microreservoirdroplets is between 20 and 90% by weight of the saturation concentrationwherein the therapeutic compound is capsaicin or a capsaicin analog or amixture thereof.
 2. The topical patch as claimed in claim 1, in whichthe therapeutic compound is capsaicin.
 3. The topical patch as claimedin claim 1, in which the concentration in the therapeutic compound inthe microreservoir droplets is between 40 and 70% by weight of thesaturation concentration.
 4. The topical patch as claimed in claim 1, inwhich the amphiphilic solvent is a butanediol, such as 1,3-butanediol,dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycoldimethyl ether, diethylene glycol monoethyl ether, diethylene glycolmonobutyl ether, propylene glycol, dipropylene glycol, carboxylic acidesters of tri- and diethylene glycol, polyethoxylated fatty alcohols of6-18 C atoms or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, or mixturesof these solvents.
 5. The topical patch of claim 4 wherein the solventis diethylene glycol monoethyl ether.
 6. The topical patch as claimed inclaim 1, in which the microreservoir droplets comprise aviscosity-increasing additive dissolved in the solvent.
 7. The topicalpatch as claimed in claim 6, in which the viscosity-increasing additiveis a cellulose derivative or a high molecular weight polyacrylic acid.8. The topical patch of claim 7, in which the viscocity-increasingadditive is ethylcellulose or hydropropylcellulose.
 9. The topical patchas claimed in claim 1, in which the proportion of the microreservoirdroplets in the matrix is less than 40% by weight, preferably less than35% by weight, in particular between 20 and 30% by weight.
 10. Thetopical patch as claimed in claim 1, in which the self-adhesive matrixcomprises an amine-resistant polysiloxane.
 11. The topical patch asclaimed in claim 10, in which the self-adhesive matrix comprises amixture of a polysiloxane of medium tack and a polysiloxane of hightack.
 12. The topical patch as claimed in claim 10, wherein the matrixcontains from about 0.5 to about 5% by weight of a silicone oil.
 13. Thetopical patch as claimed in claim 1, in which the matrix comprises 5-10%by weight of capsaicin or a capsaicin analog, 10-25% by weight ofdiethylene glycol monoethyl ether, 0-2% by weight of ethylcellulose,0-5% by weight of silicone oil, and 58-85% by weight of self-adhesivepolysiloxane and the coating weight of the matrix is between 30 and 200g/m², preferably between 50 and 120 g/m².
 14. The topical patch asclaimed in claim 1, in which the matrix consists essentially of 5-10% byweight of capsaicin or a capsaicin analog, 10-25% by weight ofdiethylene glycol monoethyl ether, 0-2% by weight of ethylcellulose,0-5% by weight of silicone oil, and 58-85% by weight of self-adhesivepolysiloxane and the coating weight of the matrix is between 30 and 200g/m², preferably between 50 and 120 g/m².
 15. The patch as claimed inclaim 1 to 14, in which the backing layer consists of a polyester film10-20 μm thick.
 16. The topical patch as claimed in claim 1, in whichthe backing layer consists of an ethylene-vinyl acetate copolymer. 17.The use of a topical patch as claimed in claim 1 for the treatment ofneuropathic pain.
 18. The topical patch as claimed in claim 1 for use inthe treatment of neuropathic pain.
 19. A method for the treatment ofneuropathic pain, in which a topical patch as claimed in claim 1containing an amount of capsaicin or capsaicin analog effective for thisuse is applied.
 20. A method for the production of a topical patch asclaimed in claim 1, which comprises dissolving the therapeutic compoundin an amphiphilic solvent, adding this solution to a solution of apolysiloxane or the matrix constituents and dispersing, coating theresulting dispersion onto a protective layer which is removable againand removing the solvent of the polysiloxane and laminating the backinglayer onto the dried matrix layer.